Epidémiologie et maîtrise de la tuberculose: situation internationale

Epidémiologie et maîtrise de la tuberculose: situation internationale Paris, 24 mars 2009 Hans L Rieder Union Internationale Contre la Tuberculose et les Maladies Respiratoires

Relationship between estimated tuberculosis incidence rates 2004 and per capita gross domestic product 2005 Tuberculosis cases per 100,000 (log scale) 1,000 500 200 100 50 20 10 5 India China France 2.5 100 200 500 1,000 2,000 5,000 10,000 20,000 50,000 GDP (in US$) per head (log scale) Janssens JP, Rieder HL. Eur Respir J 2008;32:1415-6

Using a common terminology Exposure Infection Disease Death A non-infected individual is inhaling air that contains a sufficient number of M. tuberculosis as to ensure a reasonably measurable probability of inhaling at least one infecting dose An exposed individual that has inhaled an infecting dose of M. tuberculosis that has resulted in sub-clinical replication of the latter the individual has latent (sub-clinical) infection with viable M. tuberculosis An infected individual which is unable to contain replication of M. tuberculosis to a number that causes clinically manifest tuberculosis An individual with tuberculosis who is unable to control replication of M. tuberculosis so that the resulting damage kills the host

In tuberculosis pathogenesis, the incubation period (between infection and manifest disease) is not defined and there is only partial protective immunity against reinfection

Incident cases of tuberculosis emerge unpredictably from the population prevalently infected with M tuberculosis Population including persons with and without infection with M tuberculosis

Transmission Chemotherapy Doctor's delay Prophylactic treatment Preventive therapy Patient's delay Infectious tuberculosis Exposure Subclinical infection Non-infectious tuberculosis Death BCG vaccination

An Epidemiologic Approach to Tuberculosis Interventions Reduction of the incidence of tuberculous infection Essence of the tuberculosis control strategy: identification and curative chemotherapy for cases transmitting M. tuberculosis Reduction of the prevalence of tuberculous infection Component of the tuberculosis elimination strategy: identification and preventive chemotherapy for persons already infected

Mantoux C. La Presse Médicale 1910;2:10-15

100 Age-Specific Prevalence of Tuberculous Infection in Healthy Children, Paris, 1910 Per cent reacting 80 60 40 20 0 0 5 10 15 Age (years) Mantoux C. Presse Méd 1910;2:10-13

Childhood experience predicts adult experience in every birth cohort! Mortality Andvord K F. Norsk Magasin for Lægevidenskaben 1930;91:642-60

Fate of M tuberculosis in calcified lesions Author Schmitz Rabinowitch Koenigsfeld Schroeder Opie Griffith Rubinstein Anders Saenz Total Pulmonary Lesions Sterile 10 9 - - 21 17 40 40 92 77 - - 27 16 - - 44 33 234 192 Lymphatic Lesions Sterile 16 10 30 19 18 13 61 60 91 70 17 17 - - 58 50 - - 291 239 Percentage sterile 82.1 82.1 Canetti G. Paris: Vigot Frères, 1939, 305 pp

Once infected always infected : A hypothesis not borne out by facts Kristian Andvord s observation: A case for prolonged latency with subsequent reactivation, but. George Canetti s findings tell otherwise: The immune system leads to killing of tubercle bacilli

1000 Growth of BCG in mice after sub-cutaneous vaccination 500 Spleen 300 CFU of BCG 100 50 30 Lymph nodes Lung 10 0 1 2 3 4 5 Month after BCG vaccination Olsen AW, et al. Scand J Immunol 2004;60:273-77

Protection Afforded by BCG Vaccination in British School Children During Follow-up 100 80 Protection (%) 60 40 20 0 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Year of follow-up D'Arcy Hart P, et al. Br Med J 1977;2:293-5

The Koch Phenomenon A primary infection leads to a delayed response and has often a mild and self-limited course A reinfection results commonly in a rapid response with tissue necrosis Drawings: Koch R. Mittheilungen aus dem Kaiserlichen Gesundheitsamte 1884;2:1-88. Phenomenon: Koch R. Dtsch Med Wochenschr 1891;17:101-2.

1930: Andvord Birth cohort Cross-sectional Age Morbidity / mortality Primary infection Primary infection 1891: Koch Progressive Re-infection Time 1939: Canetti Re-infection Time / age Abortive 1977: BMRC BCG Trial Time Remaining live bacilli Tissue destruction BCG protection

Occam s razor? o o o A first infection is commonly overcome and frequently ends in the elimination of bacilli but primes the immune system for a decade or more A primed immune system may protect against subsequent re-infection or alternatively results in a severe tissue damaging response A positive tuberculin skin test is neither expression of living bacilli nor of protective immunity, it only reflects the immunologic response following prior infection

Incidence Case Rate Among Household Contacts of Smear- Positive Tuberculosis, by Intitial Tuberculin and IGRA Test, Gambia Incidence per 100,000 p-yr 2000 1500 1000 500 100 Mx: ES: Mx- ES- Mantoux Elispot 0.8-1.3%! Mx- ES- Mx+ Mx+ ES- ES+ Mx- ES+ Mx+ ES+ Mx+ or ES+ Hill PC, et al. PLoS One 2008;3(1): e1379. doi:10.1371/journal.pone.0001379

A simplified view of a problem: Tuberculin skin test versus IGRAs Both tests measure the wrong thing, but IGRAs do it more specifically An immunologic response to mycobacterial antigens acquired in the past does not equate currently live bacilli ready to cause disease (BCG!)

400 Preventive Therapy for HIV Infected Police Officers in Dar es Salaam, Tanzania HIV+ Number of persons 300 200 100 Got result Accept PT Evaluated Started INH Adherent 0 Bakari M, et al. East Afr Med J 2000;77:494-7

Tuberculosis Incidence in an HIV-Infected Cohort of Patients on Anti-Retroviral Therapy, Switzerland, 1996-2005 6000 Number of Patients 5000 4000 3000 2000 1000 0 Cohort HIV pos <5mm >=5mm Prev ther Subjects 6,018 4,168 390 144 Missed 30 10 16 0 Averted 0 0.1 0.2 9.4 Total 56 9.7 Elzi L, et al. Clin Infect Dis 2007;44:94-102

Exposure Subclinical infection Effectiveness of BCG Against Meningeal Tuberculosis, Meta-Analysis of Case-Control Studies, 1947-1993 Buenos Aires, 1988 São Paulo, 1990/93 Bahia, 1991 São Paulo, 1990/93 Nagpur, 1996 Delhi, 1989 Bela Horizonte, 1988 Chennai, 1996 Summary measure Bela Horizonte, 1965 Delhi, 1964 Papua New Guinea, 1958 Delhi, 1956 Yangon, 1952 Lucknow, 1947 Infectious tuberculosis Non-infectious tuberculosis -40 0 20 50 80 90 Per cent protection (log scale) Bourdin Trunz B, et al. Lancet 2006;367:1173-80 BCG vaccination but tuberculous meningitis is no more the biggest concern in Europe

Transmission Chemotherapy Doctor's delay Prophylactic treatment Preventive therapy Patient's delay Infectious tuberculosis Exposure Subclinical infection Non-infectious tuberculosis Death BCG vaccination

Fate of Untreated Pulmonary Tuberculosis in Sanatorium Patients, Long-Term Follow-Up, Barmelweid, Switzerland 100 80 "Open" tuberculosis Per cent dead 60 40 20 "Closed" tuberculosis 0 0 2 4 6 8 10 12 14 16 18 Years after first admission Krebs W. Beitr Klin Tbk 1930;74:345-79

Fraction of cases / infected 1.0 0.8 0.6 0.4 0.2 0.0 Sensitivity of Direct Sputum Smear Examination in Identifying Pulmonary Tuberculosis and Transmitters Smear-neg Culture-pos Smear-pos Culture-pos Cases of pulmonary tuberculosis Infected contacts < 15 yr Fraction due to smear-neg cases Fraction due to smear-pos cases Calculated from data from: Grzybowski S, et al. Bull Int Union Tuberc Lung Dis 1975;50:90-106

Schematic Presentation of Relative Frequency of Patients, Number of bacilli, and Available Diagnostic Methods Improve identification of transmitters: = Improve microscopy Frequency Improve identification of patients: = Improve clinical skills 0 1 10 100 1000 10.000 100.000 1.000.000 AFB per ml of sputum Poor microscopy (35%) Excellent microscopy (65%) PCR (80%) Culture (85%) X-Ray and clinical (15%) Slide courtesy: Van Deun A, November 22, 2007

Miliary Tuberculosis After 2 months chemotherapy After 6 months chemotherapy